PocketPicker: analysis of ligand binding-sites with shape descriptors

Background  

Identification and evaluation of surface binding-pockets and occluded cavities are initial steps in protein structure-based drug design. Characterizing the active site's shape as well as the distribution of surrounding residues plays an important role for a variety of applications such as automated ligand docking or in situ modeling. Comparing the shape similarity of binding site geometries of related proteins provides further insights into the mechanisms of ligand binding.     

NIPALSTREE: a new hierarchical clustering approach for large compound libraries and its application to virtual screening

A hierarchical clustering algorithm--NIPALSTREE--was developed that is able to analyze large data sets in high-dimensional space. The result can be displayed as a dendrogram. At each tree level the algorithm projects a data set via principle component analysis onto one dimension. The data set is sorted according to this one dimension and split at the median position. To avoid distortion of clusters at the median position, the algorithm identifies a potentially more suited split point left or right of the median. The procedure is recursively applied on the resulting subsets until the maximal distance between cluster members exceeds a user-defined threshold. The approach was validated in a retrospective screening study for angiotensin converting enzyme (ACE) inhibitors. The resulting clusters were assessed for their purity and enrichment in actives belonging to this ligand class. Enrichment was observed in individual branches of the dendrogram. In further retrospective virtual screening studies employing the MDL Drug Data Report (MDDR), COBRA, and the SPECS catalog, NIPALSTREE was compared with the hierarchical k-means clustering approach. Results show that both algorithms can be used in the context of virtual screening. Intersecting the result lists obtained with both algorithms improved enrichment factors while losing only few chemotypes.     

A direct synthetic approach to novel quadrupolar [14] azolophanes

A convergent ‘3+1’ synthesis allowed a simple entrance to the first examples of [1₄] metaazolophanes 1 and [1₄](meta-ortho)₂azolophanes 2 built up from heterocyclic betaine subunits, illustrating a prototype of phanes constructed by both highly π-excessive and highly π-deficient heteroaromatic moieties linked in a 1,3-alternating fashion.     

Ground state spectroscopic constants of isothiocyanic acid,HNCS, from its microwave and millimeter wave spectra combined with far infrared data

The microwave and millimeter wave spectra of isothiocyanic acid, HNCS, in the ground vibrational state have been investigated in the frequency region 8–300 GHz. The a-type R-branch transitions have been assigned up to J = 25 and K_a = 4, and the a-type ^qQ₁ branch transitions up to J = 45. No b-type transitions could be identified in the frequency region covered. The far infrared data reported by Krakow, Lord, and Neely [J. Mol. Spectrosc., 27, 148 (1968)] were combined with our millimeter wave data in order to determine reliable spectroscopic constants. The rotational Hamiltonian, Watson's formalism with S reduction, has been extended empirically to higher order to facilitate the fitting of the large centrifugal distortion effects. The obtained constants are:

$\text{A = 1357.3 GHz; B = 5883.4627 MHz; C = 5845.6113 MHz; D}{}_{\mathrm{J}}\text{= 1.19393 kHz; D}{}_{\mathrm{JK}}\text{= ?1025.37 kHz; D}{}_{\mathrm{K}}\text{= 51.57 GHz; d}{}_1\text{= ?13.781 Hz; d}{}_2\text{= ?4.59 Hz.}$

The ¹⁴N quadrupole coupling constant has also been determined: χ_aa = 1.114 MHz.     

Millimeter-wave spectrum of isocyanamide,H2N-NC

The a-type rotational spectrum of isocyanamide was observed in the frequency range 147–300 GHz. Ether extraction of the hydrolysis products of diazomethyllithium was employed to isolate the isocyanamide. 53 rotational lines were assigned to molecules in the ground vibrational state (NH₂-inversion state 0⁺) and in the lowest excited vibrational state (NH₂-inversion state 0^?.     

Synthesis,crystal structure,and NMR spectroscopy of a 1,3,2λ5,4λ5-oxathiadiphosphetane

From the crude product of the synthesis of the dithiadiphosphetane [RP(S)S]₂ (with R = 2,4,6-iPr₃C₆H₂), the trans-oxathiadiphosphetane has been isolated, C₃₀H₄₀OP₂S₃. X-ray structure analysis and mass spectroscopic investigations give unequivocal evidence for this structure: monoclinic, C2/c (no. 15), a = 13.066(8), b = 21.726(8), c = 12.070(6) Å, β = 103.54(10)°, V = 3331 ų, Z = 4, and D_c = 1.158 g/cm³. The asymmetric unit consists of half the formula unit. Solid-state ³¹P NMR spectra give information about the chemical shift anisotropy. Results of IGLO calculations of the ³¹P nuclear magnetic shielding tensor agree satisfactorily with the experimental data. Monitoring the reaction of several dithiadiphosphetanes with benzophenone in solution by ³¹P NMR spectroscopy indicates that additional oxathiadiphosphetanes as well as thiotrimetaphosphonates are present. © 1996 John Wiley & Sons, Inc.